Journal of Neuroscience最新文献

Cocaine- and amphetamine-regulated transcript (CART) peptide has been implicated in stress-related behaviors that are regulated by central serotonergic (5-HT) systems in the dorsal raphe nucleus (DRN). Here, we aimed to investigate the interaction between CART and DRN 5-HTergic systems after initially observing CART axonal terminals in the DRN. We found that microinfusion of CART peptide _(55–102) into the DRN-induced anxiogenic effects in male C57BL/6J mice, while central administration of CART reduced c-Fos in 5-HT^DRN neurons. This inhibitory effect of exogenous CART on 5-HT^DRN activity and local 5-HT release was also demonstrated via in vivo fiber photometry coupled with calcium and 5-HT biosensors. CART inputs to the DRN were observed in various subcortical nuclei, but only those in the centrally projecting Edinger–Westphal nucleus (EWcp) were highly responsive to stress. Chemogenetic activation of these DRN-projecting CART^EWcp neurons recapitulated the effects of intra-DRN CART infusion on anxiety-like behavior in males, but not in females, suggesting a sex-specific role for this pathway. Interestingly, CART^EWcp projections to the DRN made direct synaptic contact primarily with non-5-HT neurons, which were also found to express putative CART receptors. Furthermore, chemogenetic stimulation of this CART^EWcp->DRN pathway inhibited 5-HT neurons while increasing activity in local GABAergic neurons. In summary, this study establishes for the first time a neuromodulatory role for CART^EWcp neurons in 5-HT^DRN neurotransmission and suggests that CART may drive anxiety-like behavior by promoting feedforward inhibition of 5-HT neurons.

Dopaminergic brain areas are crucial for cognition and their dysregulation is linked to neuropsychiatric disorders typically treated with pharmacological interventions. These treatments often have side effects and variable effectiveness, underscoring the need for alternatives. We introduce the first demonstration of neurofeedback using local field potentials (LFP) from the ventral tegmental area (VTA). This approach leverages the real-time temporal resolution of LFP and ability to target deep brain. In our study, two male rhesus macaque monkeys (Macaca mulatta) learned to regulate VTA beta power using a customized normalized metric to stably quantify VTA LFP signal modulation. The subjects demonstrated flexible and specific control with different strategies for specific frequency bands, revealing new insights into the plasticity of VTA neurons contributing to oscillatory activity that is functionally relevant to many aspects of cognition. Excitingly, the subjects showed transferable patterns, a key criterion for clinical applications beyond training settings. This work provides a foundation for neurofeedback-based treatments, which may be a promising alternative to conventional approaches and open new avenues for understanding and managing neuropsychiatric disorders.Significance statement This study demonstrates, for the first time, that neurofeedback using local field potentials (LFP) from the ventral tegmental area (VTA) is feasible in non-human primates. By leveraging the temporal resolution and ability to target deep brain regions, this approach provides a novel way to modulate brain activity linked to dopamine-related functions. The findings reveal that subjects can flexibly control VTA LFP signals and transfer learned strategies to new settings, offering potential for developing neurofeedback-based treatments. This research opens new avenues for managing neuropsychiatric disorders, presenting an alternative to traditional pharmacological interventions that often have side effects and limited effectiveness. The study highlights the plasticity of VTA neurons and their relevance to cognition and mood regulation.

The gustatory system allows animals to assess the nutritive value and safety of foods prior to ingestion. The first step in gustation is the interaction of taste stimuli with one or more specific sensory receptors that are generally believed to be present on the apical surface of the taste receptor cells. However, this assertion is rarely tested. We recently identified OTOP1 as a proton channel and showed that it is required for taste response to acids (sour) and ammonium. Here, we examined the cellular and subcellular localization of OTOP1 by tagging the endogenous OTOP1 protein with an N-terminal HA epitope (HA-OTOP1). Using both male and female HA-OTOP1 mice and high-resolution imaging, we show that OTOP1 is strictly localized to the apical tips of taste cells throughout the tongue and oral cavity. Interestingly, immunoreactivity is observed in the actin-rich taste pore above the tight junctions defined by zonula occludens-1 (ZO-1) and also immediately below these junctions. Surprisingly, OTOP1 immunoreactivity is not restricted to Type III taste receptor cells (TRCs) that mediate sour taste but is also observed in glia-like Type I TRCs proposed to perform housekeeping functions, a result that is corroborated by scRNA-seq data. The apical localization of OTOP1 supports the contention that OTOP1 functions as a taste receptor and suggests that OTOP1 may be accessible to orally available compounds that could act as taste modifiers.

Stimulus-driven attention allows us to react to relevant stimuli (and imminent danger!) outside our current focus of attention. But irrelevant stimuli can also disrupt attention; for example, during listening to speech. The degree to which sound captures attention is called salience, which can be estimated by existing, behaviorally validated, computational models (Huang & Elhilali, 2017). Here we examined whether neurophysiological responses to task-irrelevant sounds indicate the degree of distraction during a sustained-listening task and how much this depends on individual hearing thresholds. N = 47 Danish-speaking adults (28/19 female/male; mean age: 60.1, SD: 15.9 years) with heterogenous hearing thresholds (PTA; mean: 25.5, SD: 18.0 dbHL) listened to continuous speech while one-second-long, task-irrelevant natural sounds (distractors) of varying computed salience were presented at unpredictable times and locations. Eye tracking and electroencephalography were used to estimate pupil response and neural tracking, respectively. The task-irrelevant sounds evoked a consistent pupil response (PR), distractor-tracking (DT) and a drop of target-tracking (ΔTT), and statistical modelling of these three measures within subjects showed that all three are enhanced for sounds with higher computed salience. Participants with larger PR showed a stronger drop in target tracking (ΔTT) and performed worse in target speech comprehension. We conclude that distraction can be inferred from neurophysiological responses to task-irrelevant stimuli. These results are a first step towards neurophysiological assessment of attention dynamics during continuous listening, with potential applications in hearing-care diagnostics.Significance statement Successful speech-in-noise comprehension in daily life does not only depend on the acuity of the auditory input, but also cognitive factors like attentional control. Being able to measure distraction-dependent neurophysiological responses to peripheral, task-irrelevant stimuli would enable monitoring the extent to which the attentional focus is instantaneously captured away from a target under sustained attention. Here we show that especially pupil response and neural tracking of distractor sounds reflect the degree to which people with both normal and elevated hearing thresholds are distracted. Such a measure could be used to non-invasively track the focus of attention and thus could find application in hearing care diagnostics, where cognitive factors like attentional control are being increasingly recognized as important.

Fetal alcohol spectrum disorders (FASDs) are characterized by a range of physical, cognitive, and behavioral impairments. Determining how temporally specific alcohol exposure (AE) affects neural circuits is crucial to understanding the FASD phenotype. Third trimester AE can be modeled in rats by administering alcohol during the first two postnatal weeks, which damages the medial prefrontal cortex (mPFC) and hippocampus (HPC), structures whose functional interactions are required for working memory and executive function. Therefore, we hypothesized that AE during this period would impair working memory, disrupt choice behaviors, and alter mPFC-HPC oscillatory synchrony. To test this hypothesis, we recorded local field potentials from the mPFC and dorsal HPC as male and female AE and sham intubated (SI) rats performed a spatial working memory task in adulthood and implemented algorithms to detect vicarious trial and errors (VTEs), behaviors associated with deliberative decision-making. We found that, compared to the SI group, the AE group performed fewer VTEs and demonstrated a disturbed relationship between VTEs and choice outcomes, while spatial working memory was unimpaired. This behavioral disruption was accompanied by alterations to mPFC and HPC oscillatory activity in the theta and beta bands, respectively, and a reduced prevalence of mPFC-HPC synchronous events. When trained on multiple behavioral variables, a machine learning algorithm could accurately predict whether rats were in the AE or SI group, thus characterizing a potential phenotype following third trimester AE. Together, these findings indicate that third trimester AE disrupts mPFC-HPC oscillatory interactions and choice behaviors.Significance statement Fetal alcohol spectrum disorders (FASDs) occur at an alarmingly high rate worldwide. Prenatal alcohol exposure leads to significant perturbations in brain circuitry that are accompanied by cognitive deficits, including disrupted executive functioning and working memory. These deficits stem from structural changes within several key brain regions including the prefrontal cortex and hippocampus. To better understand the cognitive deficits observed in FASD patients, we employed a rodent model of alcohol exposure during the third trimester, a period when these regions are especially vulnerable to alcohol-induced damage. We show that alcohol exposure disrupts choice behaviors and prefrontal-hippocampal functional connectivity during a working memory task, identifying the prefrontal-hippocampal network as a potential therapeutic target in FASD treatment.

Opioids initiate dynamic maladaptation in brain reward and affect circuits that occur throughout chronic exposure and withdrawal that persist beyond cessation. Protracted abstinence is characterized by negative affective behaviors such as heightened anxiety, irritability, dysphoria, and anhedonia, which pose a significant risk factor for relapse. While the ventral tegmental area (VTA) and mu-opioid receptors (MORs) are critical for opioid reinforcement, the specific contributions of VTA^MOR neurons in mediating protracted abstinence-induced negative affect is not fully understood. In our study, we elucidate the role of VTA^MOR neurons in mediating negative affect and altered brain-wide neuronal activities following forced opioid exposure and abstinence in male and female mice. Utilizing a chronic oral morphine administration model, we observe increased social deficit, anxiety-related, and despair-like behaviors during protracted forced abstinence. VTA^MOR neurons show heightened neuronal FOS activation at the onset of withdrawal and connect to an array of brain regions that mediate reward and affective processes. Viral re-expression of MORs selectively within the VTA of MOR knockout mice demonstrates that the disrupted social interaction observed during protracted abstinence is facilitated by this neural population, without affecting other protracted abstinence behaviors. Lastly, VTA^MORs contribute to heightened neuronal FOS activation in the anterior cingulate cortex (ACC) in response to an acute morphine challenge, suggesting their unique role in modulating ACC-specific neuronal activity. These findings identify VTA^MOR neurons as critical modulators of low sociability during protracted abstinence and highlight their potential as a mechanistic target to alleviate negative affective behaviors associated with opioid abstinence.Significance statement The compelling urge for relief from negative affective states during long-term opioid abstinence presents a crucial challenge for maintaining abstinence. The ventral tegmental area (VTA) and its mu-opioid receptor-expressing (VTA^MOR) neurons represent a critical target of opioidergic action that underlie dependence and abstinence. Chronic activation of VTA^MOR neurons during opioid exposure induces maladaptations within these neurons and their structurally connected circuitries, which alter reward processing and contribute to negative affect. Using an oral morphine drinking paradigm to induce dependence, we demonstrate that withdrawal engages VTA^MOR neurons and identify this neuronal population as key mediators of opioid abstinence-induced social deficits. These findings hold promise to inform development of targeted therapies aimed at alleviating negative affective states associated with protracted opioid abstinence.

Adaptation affects neuronal responsivity and selectivity throughout the visual hierarchy. However, because most prior studies have tailored stimuli to a single brain area of interest, we have a poor understanding of how exposure to a particular image alters responsivity and tuning at different stages of visual processing. Here we assess how adaptation with naturalistic textures alters neuronal responsivity and selectivity in primary visual cortex (V1) and area V2 of macaque monkeys. Neurons in both areas respond to textures, but V2 neurons are sensitive to higher-order image statistics which do not strongly modulate V1 responsivity. We tested the specificity of adaptation in each area with textures and spectrally-matched 'noise' stimuli. Adaptation reduced responsivity in both V1 and V2, but only in V2 was the reduction dependent on the presence of higher-order texture statistics. Despite this specificity, the texture information provided by single neurons and populations was reduced after adaptation, in both V1 and V2. Our results suggest that adaptation effects for a given feature are induced at the stage of processing that tuning for that feature first arises and that stimulus-specific adaptation effects need not result in improved sensory encoding.Significance statement Nearly all sensory neurons adapt to recent input. However, how the adjustment triggered by a particular input is distributed across brain areas and how these changes contribute to sensory processing are poorly understood. Here we explore adaptation with naturalistic textures, for which neurons in primary visual cortex and area V2 have differing selectivity. Adaptation reduced responsivity in both areas, but the effects in V2 alone depended on the presence of the higher-level texture statistics to which V2 neurons are sensitive. Though prior work with simpler stimuli has argued that stimulus-specific adaptation improves stimulus discriminability, we found adaptation reduced texture information. Thus, adaptation need not improve visual encoding, suggesting its effects may serve some other purpose.

The influence of neural activity on astrocytes and their reciprocal interactions with neurons has emerged as an important modulator of synapse function. Astrocytes exhibit activity-dependent changes in gene expression, yet the molecular mechanisms by which neural activity is coupled to gene expression are not well understood. The molecular signaling pathway, Sonic hedgehog (Shh), mediates neuron-astrocyte communication and regulates the organization of cortical synapses. Here, we demonstrate that neural activity stimulates Shh signaling in cortical astrocytes and upregulates expression of Hevin and SPARC, astrocyte-derived molecules that modify synapses. Whisker stimulation in both male and female mice promotes activity-dependent Shh signaling selectively in the somatosensory, but not visual cortex, whereas sensory deprivation reduces Shh activity, demonstrating bidirectional regulation of the pathway by sensory experience. Selective loss of Shh signaling in astrocytes reduces expression of Hevin and SPARC and occludes activity-dependent synaptic plasticity. Taken together, these data identify Shh signaling as an activity-dependent, molecular signaling pathway that regulates astrocyte gene expression and promotes astrocyte modulation of synaptic plasticity.Significance statement Understanding how the nervous system orchestrates the complex cellular and molecular interactions that are necessary to adapt to changing environments is a fundamental goal in neuroscience. Neuronal adaption to novel experience is well characterized, however astrocytes are now recognized as key players in modulating synaptic function and plasticity. Like neurons, astrocytes exhibit activity-dependent gene expression. However, the mechanisms by which activity is coupled to gene expression are poorly defined. Here, we show that neural activity stimulates the molecular signaling pathway, Sonic hedgehog (Shh), in astrocytes. Shh signaling promotes expression of synapse-regulating genes and is required for astrocyte modulation of synaptic plasticity. Understanding how astrocytes contribute to synaptic plasticity sheds new light on how experience shapes brain function.

Goal-directed reaches give rise to dynamic neural activity across the brain as we move our eyes and arms, and process outcomes. High spatiotemporal resolution mapping of multiple cortical areas will improve our understanding of how these neural computations are spatially and temporally distributed across the brain. In this study, we used micro-electrocorticography (µECoG) recordings in two male monkeys performing visually guided reaches to map information related to eye movements, arm movements, and receiving rewards over primary motor cortex, premotor cortex, frontal eye field, and dorsolateral pre-frontal cortex. Time-frequency and decoding analyses revealed that eye and arm movement information shifts across brain regions during a reach, likely reflecting shifts from planning to execution. Although eye and arm movement temporally overlapped, phase clustering analyses enabled us to resolve differences in eye and arm information across brain regions. This analysis revealed that eye and arm information spatially overlapped in motor cortex, which we further confirmed by demonstrating that arm movement decoding performance from motor cortex activity was impacted by task-irrelevant eye movements. Phase clustering analyses also identified reward-related activity in the pre-frontal and premotor cortex. Our results demonstrate µECoG's strengths for functional mapping and provide further detail on the spatial distribution of eye, arm, and reward information processing distributed across frontal cortices during reaching. These insights advance our understanding of the overlapping neural computations underlying coordinated movements and reveal opportunities to leverage these signals to enhance future brain-computer interfaces.Significance statement Picking up your coffee mug requires coordinating movements of your eyes and hand and processing the outcomes of those movements. Mapping how neural activity relates to different functions helps us understand how the brain performs these computations. Many mapping techniques have limited spatial or temporal resolution, restricting our ability to dissect computations that overlap closely in space and time. We used micro-electrocorticography recordings to map neural activity across multiple cortical areas while monkeys made goal-directed reaches. These measurements revealed high spatial and temporal resolution maps of neural activity related to eye, arm, and reward information processing. These maps reveal overlapping neural computations underlying movement and open opportunities to use eye and reward information to improve therapies to restore motor function.